1. Field of the Invention
The present invention relates generally to the isolation, production, and use of growth factors. More particularly, the present invention relates to a novel therapeutic hepatokine which may be isolated and purified from mammalian cells.
Autocrine and paracrine growth factors for liver tissue are referred to generally as hepatokines. Presently known hepatokines include hepatocyte growth factor (HGF, previously referred to as hepatopoietin A), hepatopoietin B, and the like. HGF is a 728 amino acid, 83 kD heterodimeric protein which stimulates adult hepatocytes and which has been found to be identical to tumor cytotoxic factor released by embryonic lung diploid fibroblasts. Hepatopoietin B is a glycolipid having relatively weak mitogenic activity and a low molecular weight. Other cytokines having non-specific hepatocyte growth stimulating activity include epidermal growth factor (EGF), transforming growth factor-.alpha. (TGF-.alpha.), transforming growth factor-.beta. (TGF-.beta.), platelet-derived growth factor (PDGF), and acidic and basic fibroblast growth factor (FGF).
The ability to promote the growth and repair of liver cells would be of value in the treatment of a number of diseases and conditions. Liver dysfunction secondary to viral infection, alcohol abuse, and exposure to hepatotoxins, is a leading cause of morbidity and mortality. In particular, liver dysfunction is problematic because of a lack of suitable therapies.
It would therefore be desirable to provide novel hepatocyte growth factors capable of promoting the growth and repair of liver cells, particularly for the treatment of diseases, such as acute and chronic hepatitis, alcoholic liver diseases, liver dysfunction due to sepsis, exposure to toxins, and the like. Such growth factors would also be useful in conjunction with liver transplantion as well as in the culture of liver cells, particularly in conjunction with hepatocyte gene therapy.
2. Description of the Background Art
Hepatocyte growth factor (HGF) is described in Michalopoulos (1992) Hepatology 15:149-155. Hepatopoietin B is described in Michalopoulos et al. (1984) Cancer Res. 44:4414-4419. Other growth factors having hepatocyte growth stimulating activity are described in Kost et al. (1991) J. Cell Physiol. 147:274-280; Mead et al. (1989) Proc. Natl. Acad. Sci. USA 86:1558-1562; and Kan et al. (1989) Proc. Natl. Acad. Sci. USA 86:7432-7436. An assay for assessing the activity of hepatokines is reported in Tu and Wu (1990) Chinese J. Appl. Physiol. 6:199-203 and (1991) Chinese J. Pathophysiol. 7:537-541.
The full disclosures of each of the above papers are incorporated herein by reference.